ABSTRACT This Coronavirus Disease 2019 (COVID-19) supplement will study the role of neutrophil extracellular traps (NETs) as biomarkers and therapeutic targets in COVID-19. The supplement will preserve the parent project?s focus on ectoenzymes and purinergic signaling as amplifiable counterpoints to neutrophil hyperactivity and exaggerated NET release (NETosis). Indeed, elevated levels of blood neutrophils are an early indicator of SARS-CoV-2 infection, where they predict severe COVID-19 respiratory disease. Our group and others have recently revealed a critical role for NETs in various thrombo-inflammatory states including sepsis, venous thrombosis, and respiratory failure. NETs are extracellular tangles of chromatin, microbicidal proteins, and oxidant enzymes that are released by neutrophils to corral infections; however, when not properly regulated, NETs have potential to amplify inflammation and thrombosis. In COVID-19, we hypothesize that NETs will function as powerful biomarkers for predicting progression to respiratory failure. With special relevance to this application, a recent study performed in China suggested potential efficacy of the adenosine-receptor agonist, dipyridamole in severe cases of COVID-19. Dipyridamole is an FDA-approved drug that our group recently discovered?through work on the parent project?to inhibit NETosis via activation of adenosine A2A receptors (A2AR). The hypothesis here is that A2AR agonists such as dipyridamole will compensate for virus-mediated deficiencies in the pulmonary ACE2 axis and thereby suppress NETosis. This supplement requests funds to support three complementary Aims. Aim 1 will determine the extent to which NET levels can be used as predictive biomarkers in COVID-19. Aim 2 will elucidate mechanisms by which the ACE2/angiotensin-(1-7) axis regulates COVID-19 neutrophils. Finally, Aim 3 will determine the extent to which adenosine receptor agonism prevents NETosis and macrophage activation in COVID-19.